Nicotine is a highly addictive chemical present in cigarettes and other tobacco products, including smokeless tobacco products. Cigarettes are broadly considered the prototypic form of the most addictive and harmful type of tobacco product, however, addiction can develop to all presently known types of nicotine containing tobacco products, and all can be harmful. Therefore, although “cigarettes” and “smoking” are discussed throughout this disclosure, the principles and application of the resulting medicinal formulation apply to all forms of tobacco use and addiction.
Most cigarette smokers find achieving and maintaining prolonged smoking abstinence to be difficult. Research has indicated that abstaining smokers experience periodic and episodic peaks or surges of chronic craving, typically evoked by internal or external stimuli. Persons attempting to quit cigarette smoking often fail in their attempts and suffer from relapse due to the overwhelming intensity of these episodic craving peaks. There is, therefore, a need to provide a cigarette substitute which satiates these episodic craving peaks before relapse can occur.
Some acute treatments for countering cravings are behavioral. As an example, it is often recommended that smokers eat or chew something to distract their attention from their nicotine craving. Many smokers find these behavioral treatments ineffective. Also, these behavioral treatments can lead to the development of other problems, such as weight gain due to constant eating.
It has also been proposed that the administration of acute doses of nicotine could satisfy cravings, much in the manner that smoking a cigarette satiates a nicotine-withdrawal craving. Nicotine delivery systems containing actives for oral administration now include various chewing gum and lozenge formulations. Chewing gums permit release of nicotine over time as the gum product is masticated, or chewed. The action of saliva on the gum or lozenge upon ingestion further facilitates release of nicotine, as well as its subsequent absorption by the mucous membranes lining the mouth, throat, larynx and esophagus.
Nicotine is a weak base with a pKa of approximately 8.0. Absorption of nicotine into the bloodstream from the oral mucosa is highly dependent upon the concentration of un-ionized nicotine. Only un-ionized nicotine can be absorbed through the oral mucosa. Ionized nicotine cannot be absorbed and will be swallowed and mostly lost during transit through the gastrointestinal tract. Efficient mucosal absorption of nicotine may be facilitated by addition of a buffer to the gum to convert ionized nicotine to un-ionized nicotine. For example, without buffer, at a normal saliva pH of 6.5, only 3% of the available nicotine is in the un-ionized form which can be absorbed, whereas, at a buffered saliva pH of 9.0, approximately 91% of the available nicotine is in an un-ionized state which can be absorbed transmucosally. Buffer and nicotine incorporated into gum are released at the same time during chewing. An effective buffer raises the pH of saliva from a pH of approximately 6-7 to a pH of approximately 8-11. The buffer converts ionized nicotine to un-ionized nicotine that can be absorbed into the bloodstream. Thus, efficient delivery of nicotine to the bloodstream is a function of the efficiency of nicotine release and the efficiency of buffer to convert ionized nicotine to un-ionized nicotine.
A commercially available nicotine delivery gum is marketed under the trademark NICORETTE®. This commercially available gum utilizes the “chew and park” method for providing nicotine release. The consumer bites down on a piece of gum until sensing a “tingle”, then parks the gum inside the mouth for a period, and then repeats this regimen to obtain further release of nicotine. Nicotine is released in a steady, slow manner, and thus is highly dependent on conscious chewing actions by the user.
Nicotine released from NICORETTE reaches the bloodstream in several different ways. About 50% of the nicotine from the 2 and 4 milligram versions of NICORETTE is released from the gum during chewing. The rest of the nicotine typically remains in the gum and is discarded by the user. Of the nicotine delivered by the 2 milligram version of the NICORETTE gum to the saliva, about 0.8 milligram may be absorbed through the membranes of the mouth (the buccal mucosa) and appear in the bloodstream. The remaining approximately 0.2 milligram is swallowed, of which 0.06 milligram survives the first pass effects of hepatic metabolism and appears in the bloodstream. The 4 milligram version of NICORETTE gum achieves nicotine absorption values which are approximately twice those of the 2 milligram version.
Because of slow nicotine release and weak buffering action, it takes approximately 10 to 30 minutes after ingestion to achieve adequate blood levels of nicotine from NICORETTE, regardless of whether the user practices the “chew and park” (or “bite and park”) method or chews at regular intervals (e.g., one chew per 4 seconds) to relieve cravings. Although the amount of nicotine absorption from NICORETTE is related to the chewing rate and the time the saliva is held in the mouth, these variables are significant only at the extremes of rapid versus slow chewing action, and frequent versus infrequent swallowing. Outside of such extremes, these variables have very little impact on nicotine absorption.
The critical period of delay immediately following the onset of a craving, i.e., during the episodic craving peak or event, is the time the smoker experiencing a craving would normally choose to smoke a cigarette to access nicotine for relieving the craving. A product that delivers nicotine too slowly will be ineffective in relieving or satisfying the episodic craving peak or event. For example, in the case of NICORETTE, a delay of 10 minutes or more in the release and absorption of a nicotine dose comparable to the amount of nicotine derived from a cigarette may be excessively long to wait for someone who is trying to quit smoking. In practice, most commercial products simply fail to deliver an adequate dosing of the medication, especially early in the administration process, i.e., within a few minutes of administration. The result many times is a product that the smoking customer seeking to abstain from smoking finds highly ineffective in satiating his or her cravings. As a consequence, the smoker will succumb to the craving by turning to a cigarette before the medicinal nicotine delivery system has released adequate nicotine to satiate the craving.
There is consequently a need in the art for an improved delivery system for actives such as nicotine. More specifically, there is a need for an improved medicinal delivery system that provides a rapid release rate for nicotine or other medicines early in the ingestion (e.g., chewing) process, together with adequate buffering, to simulate the nicotine release of a cigarette and quench the craving of the abstaining smoker. Following an initial phase of rapid release, there is preferably a sustained release of medicine. The rapid release of medicine followed by a sustained release is referred to herein as “bi-phasic release”. There is a need in the art for a nicotine delivery product which is highly efficacious in releasing a specified, effective quantity of the active ingredient shortly after administration to provide the user with adequate blood levels of nicotine soon after onset of ingestion for suppression of cravings and withdrawal symptoms followed by sustained release of some or all of the remaining dose.
A rapid achievement of adequate blood levels of nicotine, preferably over the first five minutes of oral manipulation (e.g., chewing) would move the product toward a closer approximation of the nicotine blood levels delivered by smoking a cigarette. With a formulation that rapidly releases amounts of nicotine and buffer, preferably over the first five minutes of oral manipulation in a form that is readily absorbed into the bloodstream, the smoker can satiate and obtain relief from cravings quickly, before episodic craving peaks or events drive the smoker into relapse.